Interest in synthetic biodegradable polymers for the systemic delivery of therapeutic agents began in the early 1970's with the work of Yolles et al. on poly(lactic acid). Since that time numerous other polymers have been made and investigated for such use.
U.S. Pat. Nos. 4,093,709; 4,131,648; 4,139,344; and 4,180,646 describe biodegradable or bioerodible poly(ortho ester) polymers These polymers result from reaction of an ortho ester (or ortho carbonate) such as 2,2-diethoxytetrahydrofuran, with a diol such as 1,4-cyclohexanedicarbinol. The reaction must be carried out at elevated temperature under reduced pressure and requires a relatively long reaction time. Drug or other active agent is dispersed in the polymer and is released therefrom as the polymer biodegrades due to hydrolysis of the labile linkages
U.S. Pat. No. 4,304,767 describes another type of poly(ortho ester) which is made by reacting a polyol with a polyfunctional ketene acetal. The polymers of the present invention are also prepared using a polyfunctional ketene acetal as the starting material, but the present method is based on a two-step process whereby the polyfunctional ketene acetal is first reacted with varying molar ratios of a compound containing a vinyl ether, and the intermediate so prepared is then converted to a polymer by reaction with a polyol or polyacid. Using this procedure, polymers containing acetal, carboxy-acetal, ortho ester and carboxy-ortho ester linkages can be prepared.
Introduction of acetal, carboxy-acetal, ortho ester and carboxy-ortho ester groups between the various mer units as enabled by the presently disclosed process provides a means for controlling the rate at which the polymer biodegrades. Specifically, we have found that the rate of hydrolysis of polymers containing only acetal linkages is relatively slow while the rate of hydrolysis of polymers containing only carboxy-ortho ester linkages is very fast, with rates of hydrolysis of polymers containing only ortho ester or only carboxy-acetal linkages occupying intermediate values. Thus, by controlling the relative amounts of these four types of linkages between the various mer units, one can control the rate at which the polymer as a whole biodegrades.